Signal transduction and directional sensing in eukaryotes

Control of the cytoskeleton and mechanical contacts with the extracellular environment are essential component of motility in eukaryotic cells. In the absence of signals, cells continuously rebuild the cytoskeleton and periodically extend pseudopods or other protrusions at random membrane locations. Extracellular signals bias the direction of movement by biasing the extension of protrusions, but this involves another layer of biochemical networks for signal detection, transduction, and control of the rebuilding of the cytoskeleton. Here we develop a model for the latter processes that centers on a Ras-based module that adapts to constant extracellular signals and controls the downstream PI3K–PIP3-based module responsible for amplifying a spatial gradient of the signal. The resulting spatial gradient can lead to polarization, which enables cells to move in the preferred direction (up gradient for attractants and down-gradient for repellents). We show that the model can replicate many of the observed characteristics of the responses to cAMP stimulation for Dictyostelium, and analyze how cell geometry and signaling interact to produce the observed localization of some of the key components of the amplification module. We show how polarization can emerge without directional cues, and how it interacts with directional signals and leads to directional persistence. Since other cells such as neutrophils use similar pathways, the model is a generic one for a large class of eukaryotic cells.